This is an exciting time for research into Duchenne Muscular Dystrophy (DMD). Several companies are now testing an approach that uses a synthetic gene to replace the faulty dystrophin gene in Duchenne. This is known as gene transfer using micro-dystrophin. Or more commonly, gene therapy. The companies are using viruses to deliver the therapy.

The early data looks very promising. But there are some challenges in getting this treatment to the entire DMD population, mainly because some patients will have pre-existing antibodies to the virus’ and so will not currently be able to have the treatment.

This is why Duchenne UK has granted £655,000 to a pre-clinical DMD program with Evox Therapeutics, a company looking at using exosomes to deliver the gene without using a virus.

Exosomes are small nanometer-sized vesicles that occur naturally in cells and carry out different functions. They are essentially small sacs of membrane which carry nucleic acids and proteins. Nucleic acids are large molecules where genetic information is stored, such as DNA and RNA. Think of exosomes like little parcels which deliver information around the body.

The question we are trying to answer is ‘can exosomes be altered to deliver dystrophin mRNA or its shorter variants (often known as micro-dystrophin) to muscle cells?’. If the answer is yes, then exosomes could provide a potential new method for effectively, safely, and repeatedly delivering mRNA for dystrophin to muscles. Crucially, exosomes are far less likely to cause an immune response meaning pre-existing immunity or administration-acquired immunity should potentially be much less of an issue (see below).

The Evox team includes Professor Matthew Wood (University of Oxford), who has a wealth of experience in DMD treatment approaches and who we have worked with before exploring other treatment approaches.

Evox is engineering exosomes, the body’s natural vesicular delivery system, to enable a wide variety of drugs to reach previously inaccessible tissues and compartments, such as crossing the blood brain barrier to deliver drugs to the central nervous system, intracellular delivery of proteins, and extra-hepatic delivery of RNA therapeutics. Evox is developing its own proprietary pipeline of exosome-based therapeutics for the treatment of rare, life-threatening diseases with significant unmet need.

Part of Duchenne UK’s mission is to make sure we find and fund projects that cover all areas of research that demonstrate a potential to treat and cure DMD. We want to leave no stone unturned!

We are really excited to be supporting a project investigating a new potential method of gene therapy delivery. If successful, then we are nearer our ultimate aim of all DMD patients producing their own dystrophin

There are, however, some challenges at present in using Gene therapy as a potential treatment for DMD.

The dystrophin gene is the largest human gene and currently, it is not practical to insert the entire dystrophin gene mRNA into an Adeno-associated virus (AAV) vector (which is the method used by many of the gene therapy trials currently taking place).

As mentioned above, another challenge concerns issues with immunity. When using AAV viral vector delivery, some patients will already have a natural immunity to the virus, so their immune system would fight the virus such that it could not deliver its replacement gene therapy. In addition, all patients receiving the viral vector will develop immunity after the first dosing, so they cannot have more than one treatment. This may be a problem as the effect of the first treatment will be diluted with time and patients will require re-administration.

Our project with Evox will look at whether it is possible to deliver the dystrophin gene mRNA or its shorter variants using exosomes, as an alternative delivery method to viral vectors.

Dr Antonin de Fougerolles, Chief Executive Officer of Evox, said: “We are excited to be working with Duchenne UK on exploring a potential transformative solution to treat Duchenne patients. We will conduct research to assess the potential of our exosome drug platform to deliver functional dystrophin which is missing or defective in these patients. This work will also allow us to explore targeted delivery of exosomes to muscle which may be beneficial not only for Duchenne patients, but also ultimately for patients with other musculoskeletal diseases.”

Emily Crossley & Alex Johnson, Co-CEOs of Duchenne UK said: “We are delighted to be working with Evox to advance this potentially exciting work to help in the field of Duchenne Muscular Dystrophy. One of the most challenging aspects of using viruses to deliver gene therapy is that many patients may already have what are known as pre-existing antibodies – they are ‘resistant’ to the virus - and so the replacement gene carried by the virus will never reach its target. Exosomes could provide a potential new method for effectively, safely, and repeatedly delivering genetic material encoding for dystrophin to muscles without the problem of pre-existing antibodies.”

Duchenne UK would like to thank our partner charities for their contribution to this project: Alex’s Wish (£60,000), Caring for Connor (£5,000), Chasing Connors Cure(£20,000), Duchenne Now (£100,000), Hope for Gabriel (£5,000) and Joining Jack (£200,000)

We would like to also thank our family funds for supporting the project: Archie’s March (£5,000), Help Harry (£14,000), Hope for Harry (£10,000), Jack’s Mission (£20,000), Jacobi’s Wish (£15,000), Lifting Louis (£20,000), Project GO (£20,000), Smile With Shiv (£10,000, Team Dex (£10,000), Team Felix (£60,000) and William's Fund (£40,000).

Please watch our film which explains more about gene therapy, Evox Therapeutics, the discovery of exosomes and why this project is important and exciting:

EVOX Q&A

Q: How is this project different to gene therapy programmes?

A: There are currently several gene therapy programmes in the clinic, which all use a virus to deliver the genetic material to the patients’ cells.

However, because these viruses occur naturally, some patients may have previously been exposed to them in the environment and developed a natural resistance. In these cases, the body will produce antibodies to the virus which means upon a second exposure to the same virus, the body will recognise it and dispose of it. Patients with this resistance are said to have pre-existing antibodies. Of course, patients who have received a viral therapy and require a second dose will also have the same issues with resistance.

This project aims to investigate whether we can use a completely different system to deliver micro-dystrophin which doesn’t involve using a virus at all. Instead of using viruses we will see if we can use exosomes.

Q: What are exosomes?

A: Exosomes are small nanometer-sized vesicles (about one fortieth the diameter of a human hair) that our cells produce naturally. Think of them as tiny parcels which deliver information and instructions wherever they are needed in the body. Our bodies naturally produce millions of these every day and use them to transport proteins and other chemicals around the body

Q: What do we hope exosomes will do?

A: We hope that we can manipulate exosomes to deliver genetic material encoding micro-dystrophin to cells in the body. Exosomes could be used as an alternative to viruses for effective, safe and repeated delivery of this genetic material to muscles without the problem of pre-existing antibodies. If successful it could increase the population of DMD patients who qualify for gene therapy.

The potential advantages of exosomes as delivery vehicles for genes may not stop at reducing immune response. It is thought that we might be able to engineer exosomes to encode for the full-length dystrophin. The currently used viral delivery systems are unable to fit the genetic material of a full-length dystrophin protein, due to the exceptionally large size of the gene.

Q: If this project is successful, what will the next steps be?

A: This project is designed to determine if exosomes can be used to deliver micro-dystrophin or micro-dystrophin (or dystrophin) mRNA to muscle cells. If this is possible, we could be onto a potential new method for delivering gene therapies. Further studies would be needed to test the technology however we hope this could be brought forward into a DMD clinical trial.

- ENDS -

NOTES FOR EDITORS

What is Duchenne Muscular Dystrophy?

Duchenne Muscular Dystrophy is the most common fatal genetic disease diagnosed in childhood. Children born with DMD cannot produce the protein dystrophin which is vital for muscle strength and function. Muscle weakness starts in early childhood. Many use a wheelchair by around the age of 12. As deterioration continues it leads to paralysis and early death, often in their 20s. It almost exclusively affects boys. There is no treatment or cure. In the UK there are around 2,500 boys affected and around 300, 000 worldwide. It is classified as a rare disease.

Who are Duchenne UK?

Duchenne UK is a lean, ambitious and highly focused charity with a clear vision: to fund and accelerate treatments and a cure for Duchenne muscular dystrophy. The charity has been formed by the coming together of Joining Jack and Duchenne Children's Trust, the two biggest funders of research in the UK in the last three years. Its president is HRH The Duchess of Cornwall. Its patrons include the broadcasters Krishnan Guru-Murthy and Mary Nightingale, and the sports stars Owen Farrell, Kris Radlinski and Andy Farrell.

How to donate?

Duchenne UK is entirely reliant on donations to fund research for treatments and a cure to DMD. This can be done via:

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